Our long-term goal is to understand the molecular basis for the importance of dendritic antigen presenting cells in generating immune responses relevant to skin, hoping our discoveries lead to better treatments for inflammatory diseases. Having discovered a unique T cell inhibitory pathway, composed of DC-HIL on antigen presenting cells (APC) and its ligand syndecan-4 (SD-4) on activated T cells, that shares overlapping features with other known APC/T cell pairs of inhibitory molecules, but is distinguished by the ability to deactivate effector/memory T cells while sparing regulatory T cells, we now wish to: (1) elucidate signals within T cells triggered by binding of DC-HIL to SD-4 with a focus on CD148 phosphatase activity in human cells; (2) develop strategies employing toxin-bearing DC-HIL to treat SD-4+ T cell-mediated skin inflammation using mouse models of contact hypersensitivity; and (3) validate the differential effect of DC-HIL on effector vs. regulatory T cells in vivo using mouse models of lethal acute graft-vs.-host disease. Our new findings, in turn, should lead to application of the DCHIL/SD-4 pathway for biologic and/or pharmacologic benefit. PUBLIC HEALTH RELEVANCE: We discovered and have characterized a unique T cell inhibitory pathway composed of DC-HIL on antigen presenting cells (APC) and its ligand syndecan- 4 (SD-4) on activated T cells. This pathway is distinguished by its ability to deactivate effector/memory T cells while sparing regulatory T cells. Our proposal will: elucidate signals within T cells triggered by DC-HIL/SD-4 ligation; develop strategies employing toxin-bearing DC-HIL to treat SD-4+ T cell-mediated skin inflammation; and validate the differential effect of DC-HIL on effector vs. regulatory Tcells in vivo. Our new findings should lead to application of the DC- HIL/SD-4 pathway for biologic and/or pharmacologic benefit.